Adamantyl sulfonamide compounds



United States Patent ABSTRACT OF THE DISCLOSURE This invention relates to new adamantyl sulfonamide compounds which are useful as antimicrobial agents.

This invention relates to new compounds of the formula I n20 CH2 CH2 7 (1) wherein R and R each is hydrogen, halogen, lower alkyl, phenyl or phenyl-lower alkyl, R is hydrogen or lower alkyl, R is hydrogen, lower alkyl, lower alkoxy, halogen or halo-lower alkyl and n is 0, l or 2, and salts thereof.

The lower alkyl groups include straight and branched chain aliphatic hydrocarbon radicals such as methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, amyl and the like. Similar radicals are included in the lower alkoxy, phenyl-lower alkyl and halo-lower alkyl groups. The halolower alkyl groups include such substituents as chloromethyl, bromomethyl, dichloroethyl, trifiuoromethyl and the like. All four halogens are included but chloro and bromo are preferred as the individual halogens and trifluoromethyl is the preferred haloalkyl group.

The new compounds of Formula I are produced by condensing a compound of the formula 1 (cit -Nna R wherein R, R and R have the same meaning as in Formula I, with a p-aminobenzenesulfonyl halide of Formula III or a p-nitrobenzenesulfonyl halide of Formula IV.

R3 3 x-sM-Q-mnu XSO3NO2 (III) (IV) In Formulas III and IV, X is a halogen such as chlorine or bromine and in Formula III R is a protecting group, such as acetyl, carbethoxy or carbobenzoxy, which can be converted to an amino group by hydrolysis. If the nitro compound of Formula IV is used, the nitro group is converted to the amino group, after the condensation reaction, by reduction.Thecondensation reaction is effected in the presence of an organic base suchas pyridine or triethylamine.

The compounds of Formula I form acid addition salts with various inorganic and organic acids. Illustrative salts include the hydrohalides, e.g., hydrobromide, hydrochloride, hydroiodide, sulfate, nitrate, phosphate, borate, acetate, oxalate, tartrate, malate, citrate, succinate, benzoate, pamoate, ascorbate, salicylate, theophyllinate, camphorsulfonate, alkanesulfonate, e.g., methanesulfonate, arylsulfonate, e.g., benzenesulfonate, toluenesulfonate, etc. It is frequently convenient to elfect the purification of the product by forming the acid salt. The free base may then be obtained therefrom by neutralization with an alkali hydroxide such as ammonium hydroxide.

When R is hydrogen, the compounds of Formula I form basic salts, both inorganic and organic, e.g., salts such as alkali metal salts like sodium or potassium salts or alkanolamine salts like diethanolamine salts.

The starting amines of Formula II are prepared by reduction of the corresponding amide with lithium aluminum hydride or by the reaction of an N-alkylacylamide with halogenated adamantane, followed by hydrolysis to the N-alkyladamantaneamine. Alternatively, the group R may be' introduced after the condensation, by treating the product with an alkyl halide like methyl iodide and a base like sodium hydroxide.

The compounds of Formula III may be prepared by chlorosulphonation of the substituted N-protected amine or by treating the corresponding chlorosulphonic acid with phosphorus pentachloride.

The compounds of Formula IV may be prepared by chlorosulfonation of the substituted nitrobenzene or by treating the corresponding chlorosulfonic acid with phosphorus pentachloride.

The salts are prepared by treating a compound of Formula I with an acid, preferably a strong mineral acid, like HCl, HBr, H 50 at a temperature of about 5080.

The new compounds of this invention are useful as antimicrobial agents, e.g., as antiviral agents, for example, against influenza virus such as A-PR8 or hepatic virus such as MHV or as antibacterial agents, for example, against Staphylococci or Diplococci. They may be used as antiseptics or disinfectants for control or elimination of airborne or environmental microbes, e.g., in sprays, aqueous solutions, emulsions or suspensions of up to about 10% concentration. They may also be used orally or parenterally to com-bat microbial infestation of such organisms in animal species affected by them by oral or parenteral administration of 5 to 40 mg./ kg. three or four times daily of a compound of Formula I or a physiologically acceptable acid addition salt thereof (or basic salt when R is hydrogen) in conventional dosage forms such as tablets, capsules, injectables or the like.

EXAMPLE 1 Preparation of N -(1-adamantyl)sulfanilamide METHOD A (1) Preparation of N-(l-adamantyl)-p-nitrobenzenesulfonamide;To a solution of 11.1 g. (0.05 mole) of pnitrobenzenesulfonyl chloride in 150 ml. of anhydrous pyridine, a solution of 7.6 g. of l-aminoadamantane in ml. of pyridine is added at a slow rate. The mixture is then stirred overnight at room temperature. The solution is concentrated and poured onto ice water. The yellow solid that precipitates is collected 15 g.) and crystallized twice from dilute methanol to give 10.3 g. of the product as pale yellow crystals melting over 280.

(2) Preparation of N l-adamantyl)sulfanilamide.- A solution of 3 g. of N-(l-adamantyl)-p-nitrobenzenesulfonamide dissolved in 200- ml. of absolute alcohol (warming) is reduced catalytically using 0.3 g. of platinum oxide. After the reduction is complete, the catalyst is filtered oft 3,501,511 3 4 and the solution is concentrated in vacuo. Upon dilution Example 7. R =CH with 500 ml. of dry ether, 2.5 g. of the compound precipi- Example 8. R =OC H tates as a yellow powder. It is collected, and crystallized Example 9. R =CH from a mixture of 200 ml. of methanol and 200 ml. of Example 10. R =C H water to give 1.6 g. of N -(1-adamantyl)sulfanilamide as Example 11. R =Cl lon ellow needles, M.P. 178179. 5

g y METHOD B EXAMPLE 12 (1) Preparation of 4-(l-adamantylsulfamoyl)acetanil- Preparation of NL(l-adamantylmethyl)Sulfanilamjde ides.A solution of 9.6 g. (0.06 mole) of l-aminoada- Preparation of l-adamantalw carboxylic acid chmantane and 13.9 g. (0.06 mole) of p-N-acetylsulfanilyl 1O 6- 18 g. f l-adamantane carboxylic acid, 50 ml. chloride in 300 ml. of anhydrous pyridine is stirred at of thionyl Chl is added With Cooling, and the room temperature overnight. At the end of the period, the ture is heated under reflux for minutes. The excess of reaction mixture is heated on a steam-bath for 0.25 hour. thionyl chloride is removed in vacuo. The addition of The mixture is poured into a well-cooled solution of 5 N 2X 30 ml. of dry benzene (benzene dried over silica gel) hydrochloric acid. The solid that precipitates is collected, and evaporation serve to remove the last traces. Anhywashed with ether and crystallized from dilute methyl aldrous ether (30 ml.) is added and the solution is evapcohol to give 8.2 g. of pale yellow crystals, M.P. 211-213 orated leaving 19.2 g. (92%) of l-adamantanecarboxylic (2) Preparation of N -(1-adamantyl)sulfanilamides.- acid chloride as a brownish white solid.

A suspension of 1.0 g. of 4-(1-adamantylsulfamoyDacet- 20 (2) Preparation of 1-adamantanecarb0xamide.1- anilide in 300 ml. of 5% sodium hydroxide solution is readamantanecarboxylic acid chloride g.) dissolved in fluxed with stirring for 0.75 hour. The mixture is cooled 70 ml. of dry tetrahydrofuran, is added to a well-cooled in ice and made strongly acidic with 20% hydrochloric aqueous ammonia solution. A white precipitate appears acid. The solution is filtered, cooled and basified with 10% and the mixture is then stirred for 0.5 hour. The precipisodium hydroxide solution. The product that separates is tate is filtered, washed with water to neutrality and dried collected, and crystallized from methanol-water to give 0 over phosphorus pentoxide in vacuo to give 30.1 g. of 1- 210 mg. of needles; M.P. 176178, infrared identical to adamantanecarboxamide; M.P. l86l87.5. the material made by Method A. (3) Preparation of 1-adamantylmethylamine.To a

Following the same procedures (Method A or B) but Well-stirred suspension of 30 g. of lithium aluminum hysubstituting an equivalent amount of the indicated amino- 3O dride in 1000 ml. of dry ether, 27 g. (0.15 mole) of 1- chloride in the procedure of Example 1, the correspondadamantanecarboxamide is added in portions over 21 peing substituted sulfanilamide is obtained. riod of 1.5 hours. After the addition, the reaction mixture 1 Aminoadamantane 11 -Adamantyl sulfenilamide l A N. -so -'NH a 3 Example 2. R=H, R -=CH R =H I is stirred at room temperature for 1 hour, and then is refluxed with stirring for, 4 hours, and finally is allowed Example 4. R=H, R =H, R =CH to stand overnight at room temperature. The suspension Example 5, R=I-I, R =H, R =C H is well-cooled and ml. of Water is added dropwise with Example 6. R=F, R =OCH R =H 50 vigorous stirring. This is followedby the addition of 100 t f th ml. of 10% sodium hydroxide solution. The ethereal lay- Slmllarly by subsmutmg an eqmvalent amoun o e er is separated and the solid is extracted three times with indicated acetylsulfanilyl chloride or nitrobenzenesulfonyl chloride in the procedure of Example 1, the correspondether- The? combmed ethereal layer 15 drled s) ing substituted sulfanilamide is obtained.

Example 3. R=CH R =CH R =H Acetz l sul fony'l chloride 1 (l-adamantyl sulfanilamide clso mrcocir NHSO2 QNKZ' a R evaporated in vacuo to give 14.5 g. of l-adamantylmeth- Nitrobenzenesulfonyl chlorlde ylamine as a pale yellow liquid (4) Preparation of N (adamantylmethyl)sulfanilamide.Following the procedure of Example 1 but substi- 2- 2 tuting l-adamantylmethylamine for the l-aminoadamantane, there is obtained N -(l-adamantylmethyl)sulfanil- R3 amide.

t as starting material.

Similarly by substituting the following adamantanecarboxylic acids for l-adamantanecarboxylic acid, there is obtained the corresponding substituted N -(l-adamantylmethyl) sulfanil amides.

Adamantane carboxylic acid 5 R N l-adamantylmethyl sulfanilamides l ca mrso g EXAMPLE 17 Preparation of N -(l-adamantylethyl)sulfanilamide (1) Preparation of l-adamantylacetic acid.A solution of 25 g. of l-bromoadamantane in 100 g. of dichloroethylene is added dropwise during 1.5 hours to 100 ml. of sulfuric acid (90%) containing 18 g. of boron trifiuoride. The temperature is maintained between 810. After stirring for 3 hours at 10, crushed ice is gradually added, and the mixture diluted with water. The crude precipitate (26.5 g.) is dissolved in 10% sodium hydroxide solution, and the cloudy solution is extracted once with ether. The basic solution is cooled, and acidified with 5% hydrochloric acid. The l-adamantaneacetic acid that precipitates is collected and dried to give 21.5 g. of white solid, M.P. 130l33, the analytical sample crystallizes from methanol-water as long white needles; M.P. 134- 136.

(2) Preparation of l-adamantaneacetic acid chloride is prepared similar to l-adamantanecarboxylic acid chloride but using l-adamantaneacetic acid (Example 12, 1)

(3) Preparation of l-adamantaneacetamide is prepared similar to l-adamantanecarboxamide (Example 12, 2), M.P. 166168.

(4) Preparation of 2- (1 adamantyl)ethylamine is made similar to l-adamantylrnethylmethylamine (Example l2, 3). It may be identified as its hydrochloride which separates as white crystals from methanol-ether, M.P. over 280.

(5) Preparation of N -(l-adamantylethyl)sulfanilamide.Foll0wing the procedure of Example 1, but subsituting l adamantylethylamine for the l-aminoadamantane, there is obtained N -(l-adamantylethyl)sulfanilamide.

What is claimed is:

1. A compound of the formula R OH2OH CH2 o oHz)..-N-s02( NHz o in m H2 wherein R and R each is hydrogen, halogen lower alkyl, phenyl or phenyl-lower alkyl, R is hydrogen or lower alkyl, R is hydrogen, lower alkyl, lower alkoxy, halogen or halolower alkyl and n is 0, 1 or 2 and salts thereof.

2. A compound as in claim 1 wherein R, R R and R all are hydrogen and n is 0.

3. A compound as in claim 1 wherein R, R R and R all are hydrogen and n is 1.

4. A compound as in claim 1 wherein R, R R and R all are hydrogen and n is 2.

5. A compound as in claim 1 wherein R, R and R all are hydrogen, R is methyl and n is 0.

6. A compound as in claim 1 wherein R, R and R all are hydro-gen, R is methyl and n is 0.

7. A compound as in claim 1 wherein R, R and R all are hydrogen, R is ethyl and n is l.

8. A compound as in claim 1 wherein R, R and R all are hydrogen, R is fluorine and n is 1.

9. A compound as in claim 1 wherein R, R and R all are hydrogen, R is trifluoromethyl and n is O.

10. A compound as in claim 1 wherein R and R each is methyl, R and R each is hydrogen and n is 1.

HENRY R. JILES, Primary Examiner C. M. SHURKO, Assistant Examiner US. Cl. X.R. 

